Hard tissues in the human body, such as bone and tooth enamel, are architecturally highly complex tissues with superior strength modulus and rigidity compared to other tissues. Their formation involves specific and tightly regulated molecular events between cells and their surrounding extracellular environments. Following injury or disease, the adult human body cannot initiate molecular mechanisms for repair similar to those that occur during initial hard tissue development. The emerging field of regenerative medicine aims at the successful structural and functional replacement of tissues lost to trauma or disease. With life expectancy increasing worldwide, age related tissue degradation, injury, or disease of skeletal and dental tissues pose a significant expense to healthcare, individual productivity, and the maintenance of an active lifestyle. In response to this pressing need, breakthroughs are needed to transform the strategies used for hard tissue regeneration. Our collaborative team seeks to uncover principles governing this regenerative response in hard tissue using three-dimensional self-assembling bioactive scaffolds as a model therapeutic material. Using a multidisciplinary approach spanning the fields of nanoscience, synthetic chemistry, genetics, and developmental biology, we propose the development of highly bioactive materials containing bottom up designed nanostructures with potential to effectively regenerate bone and tooth enamel. Our team aims to accomplish three main goals: 1) use rational molecular design to optimize new materials that can trigger the regeneration of bone and enamel, including the development of artificial substitutes that emulate the architecture of hard tissue matrices; 2) improve our understanding of the cellular and molecular mechanisms operating during hard tissue development and regeneration in order to optimize clinical regenerative strategies; and 3) assess the scalability of our technology toward future clinical trials. PUBLIC HEALTH RELEVANCE: Following injury or disease in hard tissues such as bone and tooth enamel, the adult human body cannot initiate repair mechanisms similar to those that occur during development. Our collaborative team uses nanoscience, synthetic chemistry, genetics, and developmental biology to engineer biologically instructive scaffolds for cells targeting bone and enamel formation. We pursue three main goals: 1) use rational design to optimize materials for use in methods to regenerate bone and enamel; 2) identify and employ cellular and molecular mechanisms operating during hard tissue regeneration so as to optimize clinical regenerative strategies; and 3) assess the scalability of our technology toward future clinical trials.